Method of treating hepatic encephalopathy with sorbitol



United States Patent 3,522,354 METHOD OF TREATING HEPATIC ENCEPHA-LOPATHY WITH SORBITOL William Robley Ebert, Columbus, Ohio, assignor toPhilips Roxane Laboratories, Inc., Columbus, Ohio, a corporation ofDelaware No Drawing. Filed Nov. 29, 1967, Ser. No. 686,701 Int. Cl. A61k27/00 US. Cl. 424343 3 Claims ABSTRACT OF THE DISCLOSURE A method oftreating patients with hepatic encephalopathy which comprisesadministering daily to said patients a small but effective amount ofsorbitol.

This invention relates to a method of treating patients suffering fromhepatic encephalopathy.

Chronic portal-systemic (hepatic) encephalopathy, sometimes referred toas hepatic coma, is an incapacitating disease, and in many patientscontrol of neuropsychiatric symptoms remains unsatisfactory. Presenttreatment is aimed at reduction of ammonia and other nitrogenouscompounds produced in the large bowel from protein derivatives bybacterial degradation. Long term restriction of dietary proteins, onemethod of treatment, is not effective as it exaggerates an alreadyexisting negative nitrogen balance. Reduction of bacterial flora bylongcontinued administration of neornycin may be complicated bydiarrhea, steatorrhea, moniliasis and staphylococcal enterocolitis.Purgation has onlya slight effect and its use -is limited to very mildcases. Colectomy or surgical exclusion of the colon has an operativemortality of up to 50%. Therefore, it can be seen that present methodsof treating this disease have not been very successful.

It has now been found that the condition of patients suffering fromhepatic encephalopathy may be markedly improved by orally administeringto said patient a daily dosage of an effective amount of sorbitol. Thesorbitol which may be effectively employed for the purposes of thisinvention is Sorbitol U.S.P. and orally administerable compositionsthereof, for example, Sorbitol Solution, U.S.P.

It has been found that the amount of sorbitol which must be administereddaily to the patient sought to be treated hereunder is critical.Usually, in practice, the daily dosage of sorbitol which maysatisfactorily be employed in the practice of this invention will dependon the formulation employed and the patient being treated, and should besufficient to daily produce about two watery stools in said patient, thespecific dosage being adjusted according to the patient being treated.It has been found that in certain patients, daily administration of 20grams or more of sorbitol has been efiective. In those instances whereinthe sorbitol is employed in the form of Sorbitol Solution, U.S.P., from30 to 180 ml. of said Sorbitol Solution, U.S.P. administered daily hasbeen found to be effective. Preferably, from 60 to 120 ml. of SorbitolSolution, U.S.P. gives beneficial results although the other amounts arealso satisfactory.

The invention may be further illustrated by the following examples.

EXAMPLE 1 G. O. is a 62 year old male having a background ofpost-necrotic cirrhosis, inactive complicated by ascites and GIbleeding. A portacaval shunt was performed in 1963 and he experienced afew transient episodes of encephalopathy in the next two years. In 1964he began to develop a tremor of his left hand, then left side. He notedincreased ice fatiguability of his legs, left right and developed astaggering gait. These symptoms slowly progressed and he has been unableto walk without assistance for over a year now. These findings have beenconsidered to be due to cerebral degeneration related to his chronicliver disorder. In January 1967, he stopped eating meat, eggs, and subsisted mainly on potato soup, fruit, toast, jelly, butter. While on thelow protein intake, he felt he was more alert, his tremor decreased andhe could maneuver better. At the beginning of March, he began to eat athin slice of meat each evening. By the 23rd of March he had changed inthat he tended to be disagreeable, his comprehension worsened, hestarted to grimace and developed asterixis. Protein intake was decreasedto less than 20 grams per day. When symptoms worsened on this regimen hewas admitted to the hospital on Apr. 6, 1967.

The patient was placed on Sorbitol Solution, U.S.P., ml./ day. Proteinintake was increased to 45 grams/ day and was well tolerated. He has had3 brief episodes of drowsiness, incoordination in recent months. Theseusually occur when his stool number decreases from 2-4 to l or less/day. In each instance, decreased protein intake for 1 to 1 /2 days issufiicient to lead to rapid improvement. On August 24, SorbitolSolution, U.S.P. therapy was stopped and replaced by milk of magnesia,sufficient to maintain 3-4 stools/day. After 2 days he was felt to bedrowsy and less well coordinated. Protein intake was decreased, SorbitolSolution, U.S.P. therapy was restarted and he returned to his usualstate. The patient is currently on Sorbitol Solution, U.S.P., mL/day andeating about 35 to 40 grams of protein per day.

EXAMPLE 2 C. S. M., a 45-year-old white male was admitted to a LouisianaHospital in December 1964 with an upper GI hemorrhage. A diagnosis ofcirrhosis and bleeding esophageal varices was made at that time. He hadan enlarged liver and spleen and was noted to have marked weakness ofhis legs. There was a history of alcoholism but no alcohol ingestionsince 1964.

In February 1965 the patient was admitted for the first time to theDallas VA Hospital because of melena. At that time a right upper lobelesion was noted in the lungs, and active tuberculosis was established.On Apr. 22, 1965, a side-to-side porta-caval shunt, cholecystectomy andliver biopsy were performed. The biopsy diagnosis was Laennecscirrhosis. Cholelithiasis was present at operation. The patientcontinued in the hospital until Dec. 2, 1965, when his tuberculosis wasconsidered to be inactive. During his hospitalization he had one or moreepisodes of lethargy and asterixis, responding to decreasing his proteinintake. He was discharged on INH and Pyridoxine.

The patient was again admitted to the Dallas VA Hos pital on Oct. 16,1966 in hepatic pre-coma. Asterixis was present and the EEG was markedlyabnormal, suggestive of hepatic coma. The patient responded to routinetreatment for hepatic coma, and was discharged on a 70 gram proteindiet, and no medications, on October 28, 1966.

On Nov. 16, 1966, the patient was readmitted, in precoma with asterixis.At that time he was on a 70 gram pro tein diet and no medications athome. He responded well to 30 gram protein diet with no othermedications. He was discharged on a 30 gram protein diet on Nov. 29,1966.

His next admission to the Dallas VA Hospital was on Mar. 20, 1967, in anattempt to determine the patients protein tolerance. On admission theEEG was markedly abnormal, and asterixis was present. On neornycin, 4grams per day, the dietary protein was gradually raised to 70 grams,with lowering of the blood ammonia, and improvement in the EEG.Asterixis disappeared, and the patient was alert and oriented. Liverfunction tests were stable. Sorbitol Solution, U.S.P., 90 ml. per day,was begun. This had to be decreased to 60 ml. per day because ofdiarrhea, and was continued through June 11, 1967.

, Clinical status did not change significantly during this period oftime. However, immediately after stopping the Sorbitol Solution, U.S.P.,the patient became lethargic, developed asterixis, and on June 14, 1967,the EEG was markedly abnormal. At this point, the protein in the dietwas lowered to 50 grams for four days, and Sorbitol H. M., a 44 year oldmale, is a chronic alcoholic. A diagnosis of cirrhosis was made in 1958.He was first admitted to Parkland Memorial Hospital in February 1966with gastrointestinal bleeding. During this admission, he was in hepaticcoma and developed ascites. A second episode of GI bleeding andtransient coma ensued in March 1966. He was admitted to the hospitalagain in May 1966 because of increasing ascites and responded to medicaltherapy. An elective portacaval shunt was performed on June 20, 1966,and the patient was discharged from the hospital on June 27, 1966.

In September 1966, he was admitted again because of progressiveconfusion. His course was complicated by heart failure, pseudomonaspneumonia and intermittent coma. He was discharged from the hospital ona 40 gram protein diet, but was readmitted after two days at a nursinghome. The patient had been on the 40 gram protein diet for three daysprior to discharge.

After readmission in coma on Nov. 23, 1966, with neomycin and adjustmentof protein intake, he was alert and oriented by Dec. 5. Neomycin wasdecreased to 2 grams per day on Dec. 7. Protein intake was graduallyincreased to grams per day. After three days on this amount of proteinhe became confused, protein intake was stopped and he gradually improvedover the next few days. On Jan. 31, Sorbitol Solution, U.S.P., to ml.daily was instituted and the patient maintained his good clinical stateduring the nine days of Sorbitol Solution intake. Sorbitol Solution,U.S.P., was then stopped, and after five (5) days a flap was noted, onthe sixth day he became confused, disoriented but not comatose.

What is claimed is:

1. A method of treating hepatic encephalopathy which comprises orallyadministering to patients suffering from said disease a daily dosage ofat least twenty grams of sorbitol.

2. The method of claim 1, wherein the sorbitol is Sorbitol Solution,U.S.P.

3. The method of claim 1, wherein the sorbitol is Sorbitol Solution,U.S.P. in an amount of from 30 to ml.

References Cited Meyer, Current Therapy published by W. B. SaundersCompany, Philadelphia, Pa., 1964, pp. 376-379, RM 101-087.

Dispensitory of the United States of America, 25th Edition, part IIIII,1955, p. 1867.

Modern Drug Encyclopedia and Therapeutic Index, 5th Edition, February1952, published by Drug Publications, Inc., 49 W. 45th St., New York,NY.

ALBERT T. MEYERS, Primary Examiner D. M. STEPHENS, Assistant Examiner

